Breast cancer is generated when normal cells of the breast are changed by a gene mutation or by DNA damage and uncontrollably proliferated. In cancers affecting women, breast cancer has the highest incidence rate, and every year 1.3 million or more people are diagnosed with breast cancer worldwide with 450,000 or more deaths due to breast cancer (CA Cancer J Clin. 2011, 61: 69-90).
Treatment for breast cancer is broadly divided by surgery (surgical therapy), anticancer drug (hormone therapy and chemotherapy), and radiation irradiation (radiation therapy), and in many cases, treatment is performed through a combination of these methods. From gene profiling, breast cancer is classified into four subtypes, that is, (1) luminal A (hormone receptor (estrogen receptor (ER) or progesterone receptor (PR)) positive, human epidermal growth factor receptor type 2 (HER2) negative), (2) luminal B (hormone receptor positive, HER2 positive), (3) HER2 positive, and (4) triple negative in which all of ER, PR and HER2 are negative. In a case of a hormone receptor positive patient, hormone therapy such as tamoxifen and an aromatase inhibitor is performed, and in a case of a HER2 positive patient, anti HER2 therapy such as trastuzumab and lapatinib is performed. Similarly, treatment systems in accordance with the respective subtypes are established, and the concept of personalized medicines are widely used (J Clin Invest. 2011, 121: 3797-3803). On the other hand, chemotherapy is generally performed against triple negative, however there is no effective treatment at present. In addition, regarding the hormone therapy, there are not a few cases where patients have no therapeutic effect at all, or patients acquire tolerance.
From molecular biological analysis, it is reported that gene alteration of phosphatidylinositol 3-kinase (PI3K) pathway molecules occurs at high frequency in breast cancer (Breast Cancer Res. 2011, 13: 224). It is confirmed that among the gene alterations, in particular, PIK3CA mutations account for about 25% of breast cancer cases (Chin J Cancer. 2012, 31: 327-334). PIK3CA is the gene name of p110alpha which is a catalytic unit of PI3K, and a hot spot that mutations enter the helical domain and the kinase domain at high frequency is present. If the PI3K pathway is activated by these gene mutations, a serine-threonine kinase which is called Akt is subjected to phosphorylation, thereby being activated. At the downstream of Akt, a mammalian target of rapamycin (mTOR) is present. The mTOR is the serine-threonine kinase identified as a target of rapamycin, and plays a central role in the regulation of cell proliferation and survival. It is found that activation of the PI3K/Akt/mTOR pathway is extremely important as a mechanism to promote the proliferation of cancer cells (Oncologist. 2011, 16: 404-414).
It is recently reported that metformin known as a first-line drug of an agent for treating type 2 diabetes inhibits the proliferation of breast cancer cells by activating an AMP-activated protein kinase (AMPK) (Cancer Res. 2006, 66: 10269-10273). The AMPK is a highly conserved serine-threonine kinase, controls the energy metabolism in various cells, and responds by monitoring the variation of an AMP/ATP ratio in cells (Annu Rev Biochem. 1998, 67: 821-855). It is found that AMPK activation by metformin is based on a mitochondrial Complex I inhibitory effect (Diabetes Metab. 2003, 29 (4 Pt 2): 6S88-94). When an intracellular ATP level is reduced by Complex I inhibition, the AMP/ATP ratio increases, AMP is allosterically bonded to AMPK, and thus AMPK is activated. The activated AMPK inhibits a signal of mTOR through phosphorylation of a tuberous sclerosis complex 2 (TSC2) (Gene Cells. 2003, 8: 65-79). This is considered to be one of the reasons why metformin inhibits proliferation of cancer cells (Cancer Res 2007, 67: 10804-10812). From the above, it is believed that since Complex I inhibitor inhibits the PI3K/Akt/mTOR pathway, Complex I inhibitor is useful as an agent for treating breast cancer in which this pathway is activated.
As the compound having a Complex I inhibitory effect, a large number of compounds regardless of natural or non-natural compounds such as rotenone, pyridaben, bullatacin, piericidin A, capsaicin, and fenazaquin are known, and for example, it is reported that a compound of the following formula (A) has the Complex I inhibitory effect, and inhibits the proliferation of various cancer cells including breast cancer cells (Patent Document 1).
(Refer to this publication for the meanings of the symbols in the formula.)
In addition, it is reported that compounds of the following formulas (B) and (C), as an example of the compound having an AMPK activation effect, has the AMPK activation effect, and is useful for treating metabolic diseases such as type 2 diabetes, atherosclerosis, and cardiovascular disease and the like (Patent Documents 2 and 3, respectively). However, in these documents, the compound of the formula (I) of the present invention described below is not described, and there is no specific description suggesting usefulness for treatment of cancer and the like.
(Refer to the publication for the meanings of the symbols in the formulas.)